The Nutritional Prevention of Cancer (NPC) Trial, a randomized, double-blind, Phase III clinical intervention trial of oral selenium (Se) supplementation showed, on secondary analysis, a 63% reduction in prostate cancer incidence during the initial 10 years of follow up in the treatment arm (1,2). Based on these results and our own studies, we initiated a randomized, double-blind, placebo-controlled Phase llb clinical trial (the "Watchful Waiting Study", U01 CA079080) to assess whether Se supplementation has efficacy in preventing disease progression in men diagnosed with prostate cancer. The Watchful Waiting Study successfully randomized 159 men for whom baseline biopsy specimens are available as well as repeat blood samples (taken every 3 months). It remains an overarching goal to identify disease characteristics and/or blood biomarkers with greater predictive value for treatment planning because of the high treatment morbidity among men with non-life threatening disease. However with the current recommended standard of care, few men forego treatment for their disease. In the absence of better patient differentiation, ethical considerations preclude opportunity to improve upon treatment options using a watchful waiting setting. In the absence of data from trials such as the "Watchful Waiting Study" that predate the current standard of care, it will be near impossible to test the efficacy of Se supplementation as an alternative treatment for reducing risk of disease recurrence for men with clinically ambiguous disease. This study also provides an exclusive opportunity to obtain invaluable information on the natural progression of disease in a population that is getting exceedingly difficult to study. Changes in the standard of care forced the emphasis on accrual to shift to an emphasis on follow-up of patients already enrolled. Continuation of follow-up of participants already in the Watchful Waiting Study affords 90% power to detect a 31% change in PSA velocity with Se supplementation. Thus, we will have adequate power to evaluate Se as an alternative agent for men with clinically indeterminate disease or conversely, evidence that the magnitude of effect is too marginal to risk losing the benefit gained from the current standard of care. In this renewal, we propose to complete data collection on those men already enrolled, who continue to choose to forego treatment, by providing continuous and necessary follow-up of participants currently on study, without interruption of supplementation and scheduled assessments to complete the ascertainment of endpoint data to test the efficacy of Se supplementation in delaying or preventing prostate cancer. The primary objective of this study is to test the effect of Se supplementation on disease progression measured by PSA velocity. Secondary to this objective, with its unique biospecimen resource, this study is adequately powered to test several important secondary questions about the role of baseline tissue biomarker expression and serum protein/protein profiles as independent determinants of disease progression and responsiveness to Se supplementation.